Regenxbio Inc., a Maryland-based biotechnology company, announced that the US FDA has issued a Complete Response Letter (CRL) regarding the Biologics License Application (BLA) for RGX-121 (clemidsogene lanparvovec). The investigational gene therapy was being developed for the treatment of Mucopolysaccharidosis II (MPS II), also known as Hunter syndrome, a progressive and ultra-rare neurodegenerative lysosomal storage disorder. The BLA was originally accepted in May 2025 under the accelerated approval pathway.

In the CRL, the US FDA stated that the current data set did not provide substantial evidence of effectiveness to support approval. The agency’s rationale focused on three primary areas: uncertainty regarding study eligibility criteria to adequately define a neuronopathic versus attenuated patient population, the comparability of the natural history external control arm to the study population, and the appropriateness of the surrogate endpoint used. Specifically, the agency questioned whether the reduction of heparan sulfate (HS) D2S6 in the cerebrospinal fluid (CSF) is a surrogate endpoint reasonably likely to predict clinical benefit. To address these deficiencies, the FDA suggested several potential paths, including a new controlled study, the treatment of additional patients with longer-term follow-up, or the use of an untreated control arm.

The RGX-121 program

RGX-121 is designed as a one-time gene therapy utilizing an adeno-associated virus (AAV) vector to deliver the iduronate-2-sulfatase (IDS) gene directly to the central nervous system. MPS II is an X-linked recessive disease caused by a deficiency in the I2S enzyme, leading to the toxic accumulation of glycosaminoglycans (GAGs) in tissues. This accumulation results in irreversible cell and organ dysfunction, particularly within the brain. Currently, enzyme replacement therapies exist for the systemic manifestations of MPS II, but they do not effectively cross the blood-brain barrier, leaving the neurocognitive decline of the neuronopathic form as a significant unmet medical need.

The RGX-121 program has been in development for over a decade, originating from Regenxbio’s proprietary AAV platform. The company is responsible for the global regulatory strategy and development, though it has established a strategic partnership with Japan-based Nippon Shinyaku for the development and commercialization of the asset in certain territories.

The regulatory history of RGX-121 includes several expedited designations, such as Fast Track, Orphan Drug, and Regenerative Medicine Advanced Therapy (RMAT). However, RGX-121 already face a CRL that delayed the previous November 9, 2025, PDUFA date. While the company believed that additional data submitted during the BLA review cycle addressed prior agency information requests, the CRL indicates a fundamental disagreement regarding the sufficiency of the CAMPSIITE Phase I/II/III clinical trial data.

Within the competitive landscape, there are no currently approved gene therapies for MPS II. The field is characterized by high trial complexity due to the ultra-rare nature of the patient population. Regenxbio stated it plans to request a Type A meeting with the US FDA to discuss the CRL and the requirements for a BLA resubmission. The company intends to provide additional evidence from global MPS II experts and longer-term clinical data to further clarify the patient population and demonstrate effectiveness.